Aminopyrazine diol compounds as PI3K-y inhibitors

Abstract

This application relates to compounds of Formula (I): or pharmaceutically acceptable salts thereof, which are inhibitors of PI3K-γ which are useful for the treatment of disorders such as autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases.

What is claimed is: 
     
       1. A compound, selected from:
 2-(3-(5-amino-6-(1-(methyl-d3)-1H-pyrazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(3-methylisoxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(isothiazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(isothiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(3-methylisothiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(oxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(1H-pyrazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(1H-1,2,3-triazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(2H-1,2,3-triazol-2-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-(methyl-d3)phenyl)-3,3,3-trifluoropropane-1,2-diol; 
 2-(3-(5-amino-6-(3-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-(methyl-d3)phenyl)-1,1,1,4,4,4-hexafluorobutane-2,3-diol; 
 2-(3-(5-amino-6-(1-((1-methyl-1H-pyrazol-3-yl) sulfonyl) azetidin-3-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 (3-(3-amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazin-2-yl)cyclobutyl)(3-hydroxyazetidin-1-yl) methanone; and 
 2-(3-(5-amino-6-(trifluoromethyl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       2. A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. 
     
     
       3. A method of treating a disease or disorder in a patient, wherein the disease or disorder is associated with abnormal expression or activity of PI3Kγ kinase and is selected from the group consisting of colon cancer, gastric cancer, endometrial cancer, pancreatic cancer, renal cancer, breast cancer, skin cancer, head and neck squamous cell carcinoma, liver cancer, bladder cancer, astrocytoma, glioma, pancreatic cancer, and triple negative breast cancer, the method comprising administering to the patient a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       4. The method of  claim 3 , wherein the disease or disorder is colon cancer. 
     
     
       5. The method of  claim 3 , wherein the disease or disorder is gastric cancer. 
     
     
       6. The method of  claim 3 , wherein the disease or disorder is endometrial cancer. 
     
     
       7. The method of  claim 3 , wherein the disease or disorder is pancreatic cancer. 
     
     
       8. The method of  claim 3 , wherein the disease or disorder is renal cancer. 
     
     
       9. The method of  claim 3 , wherein the disease or disorder is breast cancer. 
     
     
       10. The method of  claim 3 , wherein the disease or disorder is skin cancer. 
     
     
       11. The method of  claim 3 , wherein the disease or disorder is head and neck squamous cell carcinoma. 
     
     
       12. The method of  claim 3 , wherein the disease or disorder is liver cancer. 
     
     
       13. The method of  claim 3 , wherein the disease or disorder is bladder cancer. 
     
     
       14. The method of  claim 3 , wherein the disease or disorder is astrocytoma. 
     
     
       15. The method of  claim 3 , wherein the disease or disorder is glioma. 
     
     
       16. The method of  claim 3 , wherein the disease or disorder is pancreatic cancer. 
     
     
       17. The method of  claim 3 , wherein the disease or disorder is triple negative breast cancer.